Approach Considerations

Certain lifestyle changes, such as diet and exercise, are considered first-line treatment for adolescent girls and women with polycystic ovarian syndrome (PCOS).
[41] Pharmacologic treatments are reserved for so-called metabolic derangements, such as anovulation, hirsutism, and menstrual irregularities. Medications for such conditions include oral contraceptives, metformin, prednisone, leuprolide, clomiphene, and spironolactone.

Mean platelet volume (MPV) is a marker associated with adverse cardiovascular events, and women with newly diagnosed PCOS appear to have significantly elevated MPV levels.
[47] Kabil Kucur et al reported that use of ethinyl estradiol/cyproterone acetate or metformin for the treatment of women with PCOS seemed to have similar beneficial effects in reducing MPV.
[47]

Consultation with an endocrinologist is necessary for performing an adrenocorticotropic hormone (ACTH) stimulation test or for other causes of menstrual irregularity such as thyroid disease or pituitary adenoma. A reproductive endocrinologist should be consulted if the patient is infertile and desires pregnancy.
[48]

In October 2013, the Endocrine Society released practice guidelines for the diagnosis and treatment of PCOS. The following were among their conclusions
[49] :

Use the Rotterdam criteria for diagnosing PCOS (presence of 2 of the following: androgen excess, ovulatory dysfunction, or polycystic ovaries).

In adolescents with PCOS, hyperandrogenism is central to the presentation; hormonal contraceptives and metformin are treatment options in this population.
[50]

For menstrual abnormalities and hirsutism/acne, hormonal contraceptives are first-line treatment.

For infertility, clomiphene is first-line treatment.

For metabolic/glycemic abnormalities and for improving menstrual irregularities, metformin is beneficial.

Metformin is of limited or no benefit for managing hirsutism, acne, or infertility.

Overall, thiazolidinediones have an unfavorable risk-benefit ratio.

More investigation is needed to determine the roles of weight loss and statins in PCOS.

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Lifestyle Modifications

The American College of Obstetricians and Gynecologists (ACOG) and the Society of Obstetricians and Gynaecologists of Canada (SOGC) indicate that lifestyle modifications such as weight loss and increased exercise in conjunction with a change in diet consistently reduce the risk of diabetes. This approach has been found to be comparable to or better than treatment with medication and should therefore be considered first-line treatment in managing women with polycystic ovarian syndrome (PCOS).
[2, 3] These modifications have been effective in restoring ovulatory cycles and achieving pregnancy in obese women with PCOS. Weight loss in obese women with PCOS also improves hyperandrogenic features.

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Drug Treatment

Medical management of PCOS is aimed at the treatment of metabolic derangements, anovulation, hirsutism, and menstrual irregularity. The use of insulin-sensitizing drugs to improve insulin sensitivity is associated with a reduction in circulating androgen levels, as well as improvement in both the ovulation rate and glucose tolerance.
[3] The Endocrine Society has published a clinical practice guideline on hirsutism evaluation and treatment in premenopausal women.
[51] ACOG notes that eflornithine in conjunction with laser treatment is superior to laser therapy alone in treating hirsutism.
[3]

First-line medical therapy usually consists of an oral contraceptive to induce regular menses. The contraceptive not only inhibits ovarian androgen production but also increases sex hormone-binding globulin (SHBG) production. ACOG recommends use of combination low-dose hormonal contraceptive agents for long-term management of menstrual dysfunction.
[3] If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added. Pregnancy should be excluded before therapy with oral contraceptives or androgen-blocking agents is started.

A randomized study suggested that combined metformin/letrozole and bilateral ovarian drilling are similarly effective as second-line treatment in infertile women with clomiphene citrate–resistant PCOS.
[52] In this study, 146 patients were given metformin and letrozole, and 73 underwent bilateral ovarian drilling. There was significant reduction in testosterone, fasting insulin, and ratio of fasting glucose to fasting insulin in the metformin/letrozole group. There was significant reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and ratio of LH to FSH in the bilateral drilling group. There was no significant difference between the patients in the 2 groups regarding cycle regularity, ovulation, pregnancy rate, and abortion rate.
[52]

Another study, a double-blind trial by Legro et al, found that letrozole is more effective than clomiphene in the treatment of infertility in PCOS. Based on treatment periods of up to five cycles, the study, which involved 750 anovulatory women with PCOS, found that the birth rates for letrozole and clomiphene were 27.5% and 19.1%, respectively. The rate of congenital abnormalities and the risk of pregnancy loss in the letrozole and clomiphene groups were found to be comparable, although the likelihood of twin births was lower with letrozole.
[53, 54]

Metformin

If the patient develops type 2 diabetes mellitus, consider treatment with oral antihyperglycemic drugs, such as metformin. Metformin can also be considered in other women with PCOS who are insulin resistant and therefore at risk of developing cardiovascular disease, even women without type 2 diabetes.

Clinical trials have shown that metformin can effectively reduce androgen levels, improve insulin sensitivity, and facilitate weight loss in patients with PCOS as early as adolescence.
[55, 56, 57, 58] One study concluded that the use of metformin throughout pregnancy was associated with a 9-fold decrease in gestational diabetes in women with PCOS.
[59] In addition to having the potential to reduce gestational diabetes in pregnant women with PCOS, metformin may also reduce the risk of preeclampsia in this population.
[60]

A long-term study suggested that metformin continued to improve the metabolic profile of women with PCOS over a 36-month treatment course, particularly improving circulating high-density lipoprotein cholesterol (HDL-C), diastolic blood pressure, and body mass index (BMI).
[61] However, data are insufficient as yet to recommend metformin to all women with PCOS.

Other agents

If the patient has concomitant adrenal hyperandrogenism, treatment with low-dose prednisone or dexamethasone may be considered.

Depot leuprolide acetate (Lupron) is effective in suppressing ovarian hormone production, which effectively induces menopause; therefore, this drug must be accompanied by hormone replacement therapy. This treatment approach has not gained widespread favor.

Several medications, including benzoyl peroxide, topical retinoids (Retin-A), and topical and oral antibiotics, are effective for acne treatment. Systemic isotretinoin is used for severe or refractory cases.

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FDA Safety Alerts

Statins

On March 1, 2012, the US Food and Drug Administration (FDA) updated health care professionals regarding changes to the prescribing information concerning interactions between protease inhibitors (drugs for management of human immunodeficiency virus [HIV] and hepatitis B infection) and certain statin drugs. The combination of these drugs may raise the blood levels of statins and increase the risk for myopathy. Rhabdomyolysis, the most serious form of myopathy, can cause kidney damage and lead to kidney failure, which is life threatening.
[62]

On February 28, 2012, the FDA approved important safety label changes for the class of cholesterol-lowering drugs known as statins, including removal of routine monitoring of liver enzymes. Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels was added to the statin labels. In addition, extensive contraindication and dose-limitation updates were added to the lovastatin label in situations when this drug is taken with certain medications that can increase the risk for myopathy.
[63]

On June 8, 2011, the FDA notified health care professionals of its recommendations for limiting the use of the highest approved dose (80 mg) of the cholesterol-lowering medication simvastatin (Zocor) because of increased risk of muscle damage. The FDA required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medications.
[64]

Sibutramine

On October 8, 2010, Abbott Laboratories and the FDA notified health care professionals and patients about the voluntary withdrawal of the obesity drug sibutramine (Meridia) from the US market because of clinical trial data indicating an increased risk of heart attack and stroke.
[65]

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Metabolic Derangements

In patients with polycystic ovarian syndrome (PCOS) who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. Their sex hormone–binding globulin (SHBG) levels rise, and free testosterone levels fall by 2-fold.
[66] Serum insulin and insulin-like growth factor-1 (IGF-1) levels also decrease. In patients with PCOS who are obese, weight loss is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women, thereby improving pregnancy rates, as well as improving glucose tolerance and lipid levels.
[12, 3]

The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy for metabolic complications in overweight and obese women with PCOS.
[67] A moderate amount of daily exercise increases levels of IGF-1 binding protein and decreases levels of IGF-1 by 20%. Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. A decrease of 500-1000 calories daily, along with 150 minutes of exercise per week, can cause ovulation.

Metformin, an antidiabetic drug, improves insulin resistance and decreases hyperinsulinemia in patients with PCOS.
[68] This drug also has a small but beneficial effect on metabolic syndrome, as well as potentially causing a modest reduction in androgen levels (11%).
[4] Note that women with a body mass index (BMI) greater than 37 kg/m2 may not have a good response to metformin.
[4] An Italian study of 33 patients with PCOS demonstrated that metformin affected thyroid hormone by lowering thyroid-stimulating hormone (TSH) in hypothyroid patients with PCOS, regardless of whether these individuals received levothyroxine or were untreated.
[69]

Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin therapy. The usual starting dose is 500 mg given orally twice a day. Because common adverse effects are nausea, vomiting, and diarrhea, metformin should be taken with meals. Patients who develop these adverse effects can be instructed to decrease the dosage to once a day for a week and then gradually increase the dosage. Also, inform patients that there is a high likelihood that they will have ovulatory cycles while taking metformin. The US Food and Drug Administration (FDA) has not approved metformin for this indication.

A secondary analysis of two randomized, double blind, placebo-controlled trials that included 182 children of mothers with PCOS reported that children exposed to metformin had higher BMI and increased prevalence of overweight/obesity at 4 years of age. The study found that at 4 years of age, the metformin group had higher weight z-score than the placebo group; difference in means 0.38 (0.07 to 0.69), p=0.017, and higher BMI z-score; difference in means 0.45 (0.11 to 0.78), p=0.010. There were also more overweight/obese children in the metformin group; 26 (32%) than in the placebo group; 14 (18%) at 4 years of age; odds ratio (95% CI): 2.17 (1.04 to 4.61), p=0.038. More studies are needed to examine this association.
[94]

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Anovulation

The American College of Obstetricians and Gynecologists (ACOG) and Society of Obstetricians and Gynaecologists of Canada (SOGC) recommend clomiphene citrate as first-line therapy to stimulate ovulation when fertility is desired.
[2, 3, 5]

An alternative first line therapy to stimulate ovulation is letrozole.
[54]

Second-line therapy, when clomiphene citrate fails to lead to pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery.
[2, 3] If gonadotropins are used, a low-dose regimen is recommended,
[3] and patients must be monitored with ultrasonography and laboratory studies.
[2] Note that gonadotropin therapy is expensive and is associated with an increased risk of multiple pregnancy and ovarian hyperstimulation syndrome.
[2]

Evidence suggests that metformin frequently, but not universally, improves ovulation rates and pregnancy rates in women with polycystic ovarian syndrome (PCOS), especially in obese women.
[2, 3, 70] In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.
[71] Consider the combination of metformin and clomiphene in older women with visceral obesity and clomiphene resistance.
[2] However, this combination doesn’t significantly improve the live birth rate relative to clomiphene monotherapy.
[2] Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.
[5, 72]

A study found that N-acetylcysteine may enhance the effect of clomiphene citrate in inducing ovulation in patients with PCOS.
[73]

Patients with PCOS who are infertile but desire pregnancy should be referred to a reproductive endocrinologist for further evaluation and management of infertility. Morbidly obese women with PCOS should also be referred for pregnancy risk
[2] ; metabolic surgery may be considered in morbidly obese women with PCOS, because many features of this syndrome are reversible with successful weight loss. In vitro fertilization (IVF) is reserved for women with PCOS and unsuccessful gonadotropin therapy or those with other indications for this procedure.
[2]

A study by Chen et al found that among infertile women with PCOS, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer.
[74, 75]

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Hirsutism

A clear primary treatment for hirsutism in women with polycystic ovarian syndrome (PCOS) remains lacking.
[3] However, short-term, nonpharmacologic treatments of hirsutism include shaving and the use of chemical depilatories and/or bleaching cream.
[76] Plucking or waxing unwanted hair can result in folliculitis and ingrown hairs. Long-term, more permanent measures for unwanted hairs include electrolysis and laser treatment.

Adjunctive eflornithine with laser treatment is superior to laser therapy alone in treating hirsutism.
[3] Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. This agent works by inhibiting ornithine decarboxylase, which is essential for the rapidly dividing cells of hair follicles.

Women who do not wish to become pregnant can be effectively treated for hirsutism with oral contraceptives.
[77] Oral contraceptives slow hair growth in 60-100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity. There is also a risk of thrombotic events in obese women who use oral contraceptives; therefore, the proper precautions should be exercised to prevent such events. Oral contraceptives containing cyproterone acetate are also very effective in the treatment of more severe hirsutism
[78] ; however, this combination of agents has not been approved by the FDA for use in the United States.

Antiandrogens, such as spironolactone, are effective for hirsutism.
[79] Spironolactone (50-100 mg twice daily) is an effective primary therapy for hirsutism. Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive). Adverse effects of spironolactone include gastrointestinal discomfort and irregular menstrual bleeding, which can be managed by adding an oral contraceptive.

Ovulation induction with clomiphene citrate, metformin, or both does not alter hirsutism in infertile hirsute women with PCOS.
[80]

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Diet and Activity

Patients with polycystic ovarian syndrome (PCOS) who have impaired glucose tolerance should start a comprehensive program of diet and exercise to reduce their risk of developing diabetes mellitus. Encourage moderate physical activity, provided the patient has no contraindications. Discourage smoking because of the increased risk of cardiovascular disease. In addition, obese women with PCOS can benefit from a low-calorie diet for weight reduction.

A diet patterned after the type 2 diabetes diet has been recommended for PCOS patients.
[81] This diet emphasizes increased fiber; decreased refined carbohydrates, trans fats, and saturated fats; and increased omega-3 and omega-9 fatty acids. However, in some obese patients with PCOS, weight loss has improved menstrual regularity.
[82] Omega-3 fatty acid supplementation has been shown to reduce liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis, although these effects have not yet been proven to translate into a reduction in cardiometabolic events.
[83]

Accumulating evidence suggests an association of vitamin D deficiency with metabolic syndrome. One study found insufficient levels of 25-hydroxyvitamin D (< 30 ng/mL) in almost 75% of PCOS patients, with lower levels in those with metabolic syndrome (17.3 ng/mL) than in those without metabolic syndrome (25.8 ng/mL).
[86]

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Surgical Intervention

Surgical management of polycystic ovarian syndrome (PCOS) is aimed mainly at restoring ovulation. Ovarian wedge resection has fallen out of favor because of postoperative adhesion formation and the successful introduction of ovulation-inducing medications.

Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma. According to the Society of Obstetricians and Gynaecologists of Canada (SOGC), laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, especially in the presence of other laparoscopic indications.
[2] A small French study also suggested that surgical management via ovarian drilling with hydrolaparoscopy may be beneficial in cases of PCOS that are resistant to clomiphene citrate.
[87]

Potential complications must be considered as well. These include formation of adhesions and ovarian atrophy. Multiple pregnancy rates are lower with ovarian drilling than with gonadotropin treatment (1% vs 16%, respectively), but there are ongoing concerns about the long-term effects of ovarian drilling on ovarian function.
[88]

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Long-Term Monitoring

Polycystic ovarian syndrome (PCOS) is a disease with many long-term complications. Patients need regular follow-up with their physicians for early detection and management of any untoward sequelae associated with the syndrome (see Prognosis).

Women with PCOS who conceive are at increased risk for gestational diabetes, preeclampsia, cesarean delivery, and preterm and postterm delivery. In addition, their newborns are at increased risk of being large for gestational age, but they are not at increased risk of stillbirth or neonatal death.
[89]

Participation in a peer support group may alleviate distress and improve self-management.
[90]

American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. Washington, DC: American College of Obstetricians and Gynecologists; 2009. ACOG practice bulletin; no. 108. [Full Text].

Royal College of Obstetricians and Gynaecologists. Long-term consequences of polycystic ovary syndrome. London, UK: Royal College of Obstetricians and Gynaecologists; 2007. Green-top guideline; no. 33. [Full Text].

American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. National Guideline Clearinghouse. Available at http://guideline.gov/summary/summary.aspx?doc_id=7108. Accessed: August 28, 2009.